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      Helix 3 is necessary and sufficient for prion protein's anti-Bax function.

      Journal of Neurochemistry

      metabolism, Alanine, chemistry, Amino Acid Sequence, physiology, Amino Acid Substitution, Animals, Apoptosis, Cell Line, Tumor, Cells, Cultured, Cytoprotection, genetics, Humans, Mice, Neoplasms, Nerve Degeneration, PrPC Proteins, Prion Diseases, physiopathology, Proline, Protein Structure, Secondary, bcl-2-Associated X Protein

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          Abstract

          To identify the structural elements of the prion protein (PrP) necessary for its protective function against Bcl-2 associated protein X (Bax), we performed structure-function analyses of the anti-Bax function of cytosolic PrP (CyPrP) in MCF-7 cells. Deletions of 1, 2, or 3 N-terminal Bcl-2 homology domain 2-like octapeptide repeats (BORs), but not deletion of all four BORs, abolish CyPrPs anti-Bax function. Deletion of alpha-helix 3 (PrP23-199) or further C-terminal deletions of alpha-helix 1 and 2, and beta-strand 1 and 2 (PrP23-172, PrP23-160, PrP23-143, and PrP23-127) eliminates CyPrPs protection against Bax-mediated cell death. The substitution of helix 3 amino acid residues K204, V210, and E219 by proline inhibits the anti-Bax function of CyPrP. The substitution of K204, but not V210 and E219, by alanine residues also prevents CyPrPs anti-Bax function. Expression of PrPs helix 3 displays anti-Bax activity in MCF-7 cells and in human neurons. Together, these results indicate that although the BOR domain has an influence on PrPs anti-Bax function, the helix 3 is necessary and sufficient for the anti-Bax function of CyPrP. Identification of helix 3 as the structural element for the anti-Bax function thus provides a molecular target to modulate PrPs anti-Bax function in cancer and neurodegeneration.

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          Author and article information

          Journal
          19196429
          2710996
          10.1111/j.1471-4159.2008.05851.x

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